Advertisement

Mycological Progress

, Volume 18, Issue 8, pp 1027–1037 | Cite as

Diversity and bioactivity of Armillaria sesquiterpene aryl ester natural products

  • Maximilian Dörfer
  • Markus Gressler
  • Dirk HoffmeisterEmail author
Original Article
  • 59 Downloads
Part of the following topical collections:
  1. Topical collection on Basidiomycote Mycology in honor of Franz Oberwinkler who passed away in March 2018

Abstract

Species of the basidiomycete genus Armillaria produce bioactive small molecule natural products, referred to as melleolides. With more than 70 described members, this class of natural products is a prime example for diversity-oriented biosynthesis. Chemically, they represent hybrid molecules, composed of a tricyclic, chiral sesquiterpene protoilludene alcohol, esterified with the tetraketide orsellinic acid or its derivatives. In this review article, we summarize the melleolide’s structural diversity and present—to the extent elucidated—the enzymatic basis how their backbone structures are biosynthesized and modified. We also highlight the current knowledge on their antimicrobial, phytotoxic, and cytotoxic bioactivities, along with a view on the molecular targets of the melleolides, their unparalleled structure-activity relationships, and their modes of action.

Keywords

Armillaria mellea Biosynthesis Natural product Melleolide Orsellinic acid Protoilludene Sesquiterpene 

Notes

Funding information

Studies on melleolide biosynthesis and mode of action in D.H.’s laboratory were supported by the Excellence Graduate School JSMC (Jena School for Microbial Communication) and by the Collaborative Research Center ChemBioSys (Deutsche Forschungsgemeinschaft, grant SFB1127).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Abraham WR (2001) Bioactive sesquiterpenes produced by fungi: are they useful for humans as well? Curr Med Chem 8:583–606CrossRefGoogle Scholar
  2. Arnone A, Cardillo R, Nasini G (1986) Structures of melleolides B-D, three antibacterial sesquiterpenoids from Armillaria mellea. Phytochemistry 25:471–474CrossRefGoogle Scholar
  3. Arnone A, Cardillo R, Nasini G (1988a) Isolation and structure elucidation of melleolides I and J and armellides A and B, novel sesquiterpenoid aryl esters from Armillaria novae-zelandiae. Gazz Chim Ital 118:523–527Google Scholar
  4. Arnone A, Cardillo R, Nasini G (1988b) Secondary mould metabolites part 19: structure elucidation and absolute configuration of melledonals B and C, novel antibacterial sesquiterpenoids from Armillaria mellea. X-ray molecular structure of Melledonal C. J Chem Soc Perkin Trans 1 I:503–510CrossRefGoogle Scholar
  5. Arnone A, Nasini G, Di Modugno V, Cardillo R (1988c) Isolation and structure elucidation of melledonals D and E and melleolides E-H, novel sesquiterpenoid aryl esters from Clitocybe elegans and Armillaria mellea. Gazz Chim Ital 118:517–521Google Scholar
  6. Baumgartner K, Coetzee MP, Hoffmeister D (2011) Secrets of the subterranean pathosystem of Armillaria. Mol Plant Pathol 12:515–534CrossRefGoogle Scholar
  7. Bohnert M, Miethbauer S, Dahse HM, Ziemen J, Nett M, Hoffmeister D (2011) In vitro cytotoxicity of melleolide antibiotics: structural and mechanistic aspects. Bioorg Med Chem Lett 21:2003–2006CrossRefGoogle Scholar
  8. Bohnert M, Nützmann HW, Schroeckh V, Horn F, Dahse HM, Brakhage AA, Hoffmeister D (2014a) Cytotoxic and antifungal activities of melleolide antibiotics follow dissimilar structure–activity relationships. Phytochemistry 105:101–108CrossRefGoogle Scholar
  9. Bohnert M, Scherer O, Wiechmann K, König S, Dahse HM, Hoffmeister D, Werz O (2014b) Melleolides induce rapid cell death in human primary monocytes and cancer cells. Bioorg Med Chem 22:3856–3861CrossRefGoogle Scholar
  10. Braesel J, Fricke J, Schwenk D, Hoffmeister D (2017) Biochemical and genetic basis of orsellinic acid biosynthesis and prenylation in a stereaceous basidiomycete. Fungal Genet Biol 98:12–19CrossRefGoogle Scholar
  11. Brazee NJ, Ortiz-Santana B, Banik MT, Lindner DL (2012) Armillaria altimontana, a new species from the western interior of North America. Mycologia 104:1200–1205CrossRefGoogle Scholar
  12. Chen CC, Kuo YH, Cheng JJ, Sung PJ, Ni CL, Chen CC, Shen CC (2015) Three new sesquiterpene aryl esters from the mycelium of Armillaria mellea. Molecules 20:9994–10003CrossRefGoogle Scholar
  13. Collins C, Keane TM, Turner DJ, O’Keeffe G, Fitzpatrick DA, Doyle S (2013) Genomic and proteomic dissection of the ubiquitous plant pathogen, Armillaria mellea: toward a new infection model system. J Proteome Res 12:2552–2570CrossRefGoogle Scholar
  14. Cremin P, Donnelly DMX, Wolfender JL, Hostettmann K (1995) Liquid chromatography–thermospray mass spectrometric analysis of sesquiterpenes of Armillaria (Eumycota: Basidiomycotina) species. J Chromatogr A 710:273–285CrossRefGoogle Scholar
  15. Cremin P, Guiry PJ, Wolfender JL, Hostettmann K, Donnelly DMX (2000) A liquid chromatography–thermospray ionisation–mass spectrometry guided isolation of a new sesquiterpene aryl ester from Armillaria novae-zelandiae. J Chem Soc Perkin Trans 1:2325–2329CrossRefGoogle Scholar
  16. Donnelly DMX, Sanada S, O’Reilly J, Polonsky J, Prangé T, Pascard CJ (1982) Isolation and structure (X-ray analysis) of the orsellinate of armillol, a new antibacterial metabolite from Armillaria mellea. J Chem Soc Chem Comm 135–137Google Scholar
  17. Donnelly DMX, Polonsky J, Prangé T, Snatzke, G, Wagner U (1984) The absolute configuration of the orsellinate of armillol; application of the coupled oscillator theory. J Chem Soc Chem Comm 222–223Google Scholar
  18. Donnelly DMX, Abe F, Coveney D, Fukuda N, O’Reilly J, Polonsky J, Prangé T (1985a) Antibacterial sesquiterpene aryl esters from Armillaria mellea. J Nat Prod 48:10–16CrossRefGoogle Scholar
  19. Donnelly DMX, Coveney DJ, Polonsky J (1985b) Melledonal and melledonol, sesquiterpene esters from Armillaria mellea. Tetrahedron Lett 26:5343–5344CrossRefGoogle Scholar
  20. Donnelly DMX, Coveney DJ, Fukuda N, Polonsky J (1986) New sesquiterpene aryl esters from Armillaria mellea. J Nat Prod 49:111–116CrossRefGoogle Scholar
  21. Donnelly DMX, Coveney DJ (1987) Antibacterial sesquiterpene aryl esters from Armillaria mellea. In: Hostettmann K, Lea PJ (eds) Biologically active natural products. Clarendon Press, Oxford, pp 19–32Google Scholar
  22. Donnelly DMX, Quigley PF, Coveney DJ, Polonsky J (1987) Two new sesquiterpene esters from Armillaria mellea. Phytochemistry 26:3075–3077CrossRefGoogle Scholar
  23. Donnelly DMX, Hutchinson RM (1990) Armillane, a saturated sesquiterpene ester from Armillaria mellea. Phytochemistry 29:179–182CrossRefGoogle Scholar
  24. Donnelly DMX, Hutchinson RM, Coveney DJ, Yonemitsu M (1990) Sesquiterpene aryl esters from Armillaria mellea. Phytochemistry 29:2569–2572CrossRefGoogle Scholar
  25. Donnelly DMX, Konishi T, Dunne O, Cremin P (1997) Sesquiterpene aryl esters from Armillaria tabescens. Phytochemistry 44:1473–1478CrossRefGoogle Scholar
  26. Dörfer M, Heine D, König S, Gore S, Werz O, Hertweck C, Gressler M, Hoffmeister D (2019) Melleolides impact fungal translation via Elongation Factor 2. Org Biomol Chem 17:4906–4916CrossRefGoogle Scholar
  27. Engels B, Heinig U, Grothe T, Stadler M, Jennewein S (2011) Cloning and characterization of an Armillaria gallica cDNA encoding protoilludene synthase, which catalyzes the first committed step in the synthesis of antimicrobial melleolides. J Biol Chem 286:6871–6878CrossRefGoogle Scholar
  28. Engels B (2013) Untersuchungen zur Biosynthese sesquiterpenoider Naturstoffe, der Melleolide. In Armillaria gallica. Dissertation, RWTH AachenGoogle Scholar
  29. Firn RD, Jones GC (2003) Natural products – a simple model to explain chemical diversity. Nat Prod Rep 20:382–391CrossRefGoogle Scholar
  30. Firn RD, Jones GC (2009) A Darwinian view of metabolism: molecular properties determine fitness. J Exp Bot 60:719–726CrossRefGoogle Scholar
  31. Gill M, Steglich W (1987) Pigments of fungi (Macromycetes). Prog Chem Org Nat Prod 51:1–317Google Scholar
  32. Gill M (2003) Pigments of fungi (Macromycetes). Nat Prod Rep 20:615–639CrossRefGoogle Scholar
  33. Hovey MT, Cohen DT, Walden DM, Cheong PH, Scheidt KA (2017) A carbene catalysis strategy for the synthesis of protoilludane natural products. Angew Chem Int Ed 56:9864–9867CrossRefGoogle Scholar
  34. Jiang MY, Feng T, Liu JK (2011) N-containing compounds of macromycetes. Nat Prod Rep 28:783–808CrossRefGoogle Scholar
  35. Kobori H, Sekiya A, Suzuki T, Choi JH, Hirai H, Kawagishi H (2015) Bioactive sesquiterpene aryl esters from the culture broth of Armillaria sp. J Nat Prod 78:163–167CrossRefGoogle Scholar
  36. Koch RA, Wilson AW, Séné O, Henkel TW, Aime MC (2017) Resolved phylogeny and biogeography of the root pathogen Armillaria and its gasteroid relative, Guyanagaster. BMC Evol Biol 17:33CrossRefGoogle Scholar
  37. König S, Romp E, Krauth V, Rühl M, Dörfer M, Liening S, Hofmann B, Häfner AK, Steinhilber D, Karas M, Garscha U, Hoffmeister D, Werz O (2019) Melleolides from honey mushroom inhibit 5-lipoxygenase via Cys159. Cell Chem Biol 26:60–70CrossRefGoogle Scholar
  38. Lackner G, Bohnert M, Wick J, Hoffmeister D (2013) Assembly of melleolide antibiotics involves a polyketide synthase with cross-coupling activity. Chem Biol 20:1101–1106CrossRefGoogle Scholar
  39. Li Z, Wang Y, Jiang B, Li W, Zheng L, Yang X, Bao Y, Sun L, Huang Y, Li Y (2016) Structure, cytotoxic activity and mechanism of protoilludane sesquiterpene aryl esters from the mycelium of Armillaria mellea. J Ethnopharmacol 184:119–127CrossRefGoogle Scholar
  40. McMorris TC, Nair MSR, Anchel M (1967) The structure of illudol, a sesquiterpenoid triol from Clitocybe illudens. J Am Chem Soc 89:4562–4563CrossRefGoogle Scholar
  41. Midland SL, Izac RR, Wing RM, Zaki AL, Munnecke DE, Sims JJ (1982) Melleolide, a new antibiotic from Armillaria mellea. Tetrahedron Lett 23:2515–2518CrossRefGoogle Scholar
  42. Misiek M, Williams J, Schmich K, Hüttel W, Merfort I, Salomon CE, Aldrich CC, Hoffmeister D (2009) Structure and cytotoxicity of arnamial and related fungal sesquiterpene aryl esters. J Nat Prod 72:1888–1891CrossRefGoogle Scholar
  43. Misiek M, Braesel J, Hoffmeister D (2011) Characterization of the ArmA adenylation domain implies a more diverse secondary metabolism in the genus Armillaria. Fungal Biol 115:775–781CrossRefGoogle Scholar
  44. Misiek M, Hoffmeister D (2012) Sesquiterpene aryl ester natural products in North American Armillaria species. Mycol Prog 11:7–15CrossRefGoogle Scholar
  45. Momose I, Sekizawa R, Hosokawa N, Iinuma H, Matsui S, Nakamura H, Naganawa H, Hamada M, Takeuchi T (2000) Melleolides K, L and M, new melleolides from Armillariella mellea. J Antibiot 53:137–143CrossRefGoogle Scholar
  46. Obuchi T, Kondoh H, Watanabe N, Tamai M, Omura S, Yang JS, Liang XT (1990) Armillaric acid, a new antibiotic produced by Armillaria mellea. Planta Med 56:198–201CrossRefGoogle Scholar
  47. Oduro KA, Munnecke DE, Sims JJ, Keen NT (1976) Isolation of antibiotics produced in culture by Armillaria mellea. Trans Br Mycol Soc 66:195–199CrossRefGoogle Scholar
  48. Oppermann A (1951) Das antibiotische Verhalten einiger holzzersetzender Basidiomyceten zueinander und zu Bakterien. Arch Mikrobiol 16:364–409CrossRefGoogle Scholar
  49. Peipp H, Sonnenbichler J (1992) Secondary fungal metabolites and their biological activities, II. Occurrence of antibiotic compounds in cultures of Armillaria ostoyae growing in the presence of an antagonistic fungus or host plant cells. Biol Chem Hoppe Seyler 373:675–683CrossRefGoogle Scholar
  50. Sandargo B, Chepkirui C, Cheng T, Chaverra-Munoz L, Thongbai B, Stadler M, Hüttel S (2019) Biological and chemical diversity go hand in hand: Basidiomycota as source of new pharmaceuticals and agrochemicals. Biotechnol Adv.  https://doi.org/10.1016/j.biotechadv.2019.01.011
  51. Schroeckh V, Scherlach K, Nützmann HW, Shelest E, Schmidt-Heck W, Schümann J, Martin K, Hertweck C, Brakhage AA (2009) Intimate bacterial-fungal interaction triggers biosynthesis of archetypal polyketides in Aspergillus nidulans. Proc Natl Acad Sci U S A 106:14558–14563CrossRefGoogle Scholar
  52. Shen B (2003) Polyketide biosynthesis beyond the type I, II and III polyketide synthase paradigms. Curr Opin Chem Biol 7:285–295CrossRefGoogle Scholar
  53. Sonnenbichler J, Guillaumin JJ, Peipp H, Schwarz D (1997) Secondary metabolites from dual cultures of genetically different Armillaria isolates. Eur J Forest Path 27:241–249CrossRefGoogle Scholar
  54. Wang C, Guo S, Chen X, Ca W, Xu J, Xiao P (1996) Studies on the contents of armillarin and melleolide at different stages of development of Armillaria mellea. Zhongguo Zhong Yao Za Zhi 21:274–276Google Scholar
  55. Wick J, Heine D, Lackner G, Misiek M, Tauber J, Jagusch H, Hertweck C, Hoffmeister D (2016) A fivefold parallelized biosynthetic process secures chlorination of Armillaria mellea (honey mushroom) toxins. Appl Environ Microbiol 82:1196–1204CrossRefGoogle Scholar
  56. Yamazaki M, Matsuo M, Shibata S (1965) Biosynthesis of lichen depsides, lecanoric acid and atranorin. Chem Pharm Bull 13:1015–1017CrossRefGoogle Scholar
  57. Yang JS, Chen Y, Feng X, Yu D, Liang X (1984) Chemical constituents of Armillaria mellea mycelium I. Isolation and characterization of armillarin and armillaridin. Planta Med 50:288–290CrossRefGoogle Scholar
  58. Yang JS, Cong PZ (1988) Mass spectrometric studies on the sesquiterpenol aromatic esters from mycelium of Armillaria mellea. Acta Chim Sin 46:1093–1100Google Scholar
  59. Yang JS, Chen YW, Zeng XZ, Yu DQ, He CH, Zheng QT, Yang J, Liang XT (1989a) Isolation and structure elucidation of armillaricin. Planta Med 55:564–565CrossRefGoogle Scholar
  60. Yang JS, Su YL, Wang YL, Feng XZ, Yu DQ, Cong PZ, Tamai M, Obuchi T, Kondoh H, Liang XT (1989b) Isolation and structures of two new sesquiterpenoid aromatic esters: armillarigin and armillarikin. Planta Med 55:479–481CrossRefGoogle Scholar
  61. Yang JS, Su YL, Wang YL, Feng XZ, Yu DQ, Liang XT, He CH, Zheng QT, Yang JJ, Yang J (1990a) Chemical constituents of Armillaria mellea mycelium VI. Isolation and structure of armillaripin. Acta Pharm Sin 25:353–356Google Scholar
  62. Yang JS, Su YL, Wang YL, Feng XZ, Yu DQ, Liang XT (1990b) Studies on the chemical constituents of Armillaria mellea mycelium V. Isolation and characterization of armillarin and armillarinin. Acta Pharm Sin 24:24–28Google Scholar
  63. Yang JS, Su YL, Wang YL, Feng XZ, Yu DQ, Liang XT (1991a) Chemical constituents of Armillaria mellea mycelium VII. Isolation and characterization of chemical constituents of the acetone extract. Acta Pharm Sin 26:117–122Google Scholar
  64. Yang JS, Su YL, Wang YL, Feng XZ, Yu DQ, Liang XT (1991b) Two novel protoilludane norsesquiterpenoid esters, armillasin and armillatin from Armillaria mellea. Planta Med 57:478–480CrossRefGoogle Scholar
  65. Yang JS, Su YL, Yu DQ, Liang XT (1993) Carbon-13 nuclear magnetic resonance spectra of some protoilludane sesquiterpenoid aromatic esters from Armillaria mellea. J Chin Pharm Sci 2:11–17Google Scholar
  66. Zhou ZY, Liu JK (2010) Pigments of fungi (macromycetes). Nat Prod Rep 27:1531–1570CrossRefGoogle Scholar
  67. Zjawiony JK (2004) Biologically active compounds from Aphyllophorales (polypore) fungi. J Nat Prod 67:300–310CrossRefGoogle Scholar

Copyright information

© German Mycological Society and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department Pharmaceutical Microbiology at the Hans-Knöll-InstituteFriedrich-Schiller-UniversitätJenaGermany

Personalised recommendations